The aim of this study was to investigate the effects of stem cell factor (SCF) on interstitial cell of Cajal (ICC) depletion in the colon of diabetic mice. Male C57/BL6 mice were treated by a single intraperitoneally injected dose of streptozotocin, and those displaying sustained high blood glucose were selected as diabetes mellitus models. Six groups of mice were used: three groups of normal nondiabetic mice (untreated and treated with IgG or SCF antibody), and three groups of diabetic mice (untreated and treated with vehicle or SCF). Changes of the ICC quantities were analyzed by immunohistochemistry. ICC morphologies were observed with transmission electron microscopy. The SCF levels in sera and colon tissues were detected by ELISA and Western blot, respectively. The nondiabetic mice treated with SCF antibody and the untreated diabetic mice showed decreased SCF levels in the sera and colonic tissues, reduced numbers of ICC, and pathological changes of the ICC ultrastructures, whereas the nondiabetic mice treated with mouse IgG showed no significant changes compared with the nondiabetic mice. The diabetic mice treated with exogenous SCF showed restored SCF levels in both sera and colon tissues and improvement in the numbers of ICC and the damages of ICC ultrastructures, whereas the vehicle control of diabetic mice showed no significant changes compared with the diabetic mice. The blood glucose remained high and unchanged with the treatment of SCF or vehicle in the diabetic mice. These results indicate that diabetic mice show a decline in the number of ICC and impairment in the ultrastructures of ICC, and these abnormalities are attributed to a deficiency in the endogenous SCF but are not related to hyperglycemia. Exogenous SCF partially reverses the pathological changes of ICC in diabetic mice.